SK612000A3 - Application of insulin sensitiser, insulin secretagogue and alpha glucosidase inhibitor antihyperglycaemic agent for the treatment of diabetes mellitus and conditions associated with diabetes mellitus and a pharmaceutical composition - Google Patents

Abstract

A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, an insulin secretagogue and an alpha glucosidase inhibitor antihyperglycaemic agent, to amammal in need thereof; and composition for use in such method.

Description

Use of an insulin sensitizer, an insulin secretion promoter and an α-glucosidase inhibitor antihyperglycaemic agent for the treatment of diabetes mellitus (NIDDM, type II diabetes) and conditions associated with diabetes mellitus.

BACKGROUND OF THE INVENTION

Insulin secretion promoters are compounds that promote increased insulin secretion by pancreatic beta cells.

Known examples of insulin secretion promoters are sulfonylureas. Sulfonylureas act as hypoglycaemic agents and are used in the treatment of NIDDM (type II diabetes). Examples of sulfonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide.

α-Glucosidase inhibitory antihyperglycaemic agents such as acarbose, emiglitate and muglitol are commonly used in treatment II. type diabetes.

European Patent Application Publication No. 0,306,228 relates to certain thiazolidinedione derivatives reported to have hypoglycaemic and hypolipidemic effects. One specific thiazolidinedione disclosed in EP 0 306 228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione (hereinafter referred to as compound (I)). WO94 / 05659 discloses certain salts of compound (I), including maleate.

Compound (I) is an example of a class of anti-hyperglycemic agents known as insulin sensitizers. Compound (I) is then a thiazolidinedione insulin sensitizer.

European patent applications, publication numbers 0 008 203, 0 139 421, 0 032 128, 0 428 312, 0 489 663, 0 155 845, 0 257 781, 0 208 420, 0 177 353, 0 319 189, 0 332 331, 0 330 332, 0 528 734, 0 508 740; European applications

U.S. Pat. Nos. 5,104,888 and 5,478,852 also disclose some thiazolidinedione insulin sensitizers.

Another class of compounds generally classified as insulin sensitizing agents are those characterized by the compounds disclosed in International Patent Application Publication Nos. WO93 / 21166 and WO94 / 01420. These compounds are referred to herein as acyclic insulin sensitizers. Further examples of acyclic insulin sensitisers are disclosed in U.S. Patent 5,232,945 and International Patent Applications, Publication Nos. WO92 / 03255 and WO91 / 19702.

Examples of other insulin sensitizers are disclosed in European Patent Application, Publication Number 0 533 933, Japanese Patent Application Publication No. 05 271 204, and US Patent 5,264,451.

These publications are incorporated herein by reference.

At present, it has surprisingly been shown that Compound (I) in combination with an insulin secretion promoter and an α-glucosidase inhibitory antihyperglycaemic agent is particularly beneficial in controlling glycaemia. Such a combination is therefore particularly useful for the treatment of diabetes mellitus, especially II. type of diabetes mellitus; and conditions associated with diabetes mellitus. Treatment has also been shown to be associated with only minor side effects.

SUMMARY OF THE INVENTION

The present invention provides the use of an insulin sensitizer, an insulin secretion promoter, and an α-glucosidase inhibitor antihyperglycaemic agent for the manufacture of a medicament for the treatment of diabetes mellitus, in particular II. type diabetes.

The method comprises or co-administering sequentially the insulin sensitizer, the insulin secretion promoter and the α-glucosidase inhibitor antihyperglycaemic agent.

Co-administration includes administration of a composition comprising an insulin sensitizer, an insulin secretion promoter and an α-glucosidase inhibitory anti-3-hyperglycemic agent, or administration, substantially concurrently, of separate formulations of each active agent.

A preferred insulin sensitizer is a thiazolidinedione insulin sensitizer.

A preferred thiazolidinedione insulin sensitizer is Compound (I).

Other preferred thiazolidinedione insulin sensitizers include: (+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione - troglitazone

5- (4 - ((1-methylcyclohexyl) methoxy] benzyl] thiazolidin-2,4-dione-ciglitazone, 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidin-2, 4-dione - pioglitazone, or

5 - [(2-Benzyl-2,3-dihydrobenzopyran) -5-ylmethyl] thiazolidin-2,4-dione-englitazone.

Preferred insulin secretion promoters are sulfonylureas.

Preferred sulfonylureas include compounds referred to as glibenclamide, glipizide, glimepiride, tolazamide and tolbutamide.

Other sulfonylureas include acetohexamide, carbutamide, chloropropamide, glibornuride, glicvidone, glisentide, glisoxepide, glyclopyamide and glycylamide.

Other preferred insulin secretion promoters include repaglinide.

A preferred α-glucosidase inhibitor antihyperglycaemic agent is acarbose.

Other preferred α-glucosidase inhibitory antihyperglycaemic agents are emiglitate and miglitol.

In one embodiment, said use comprises administering 2 to 12 mg of Compound (I), especially when administered daily.

The use further includes administering 2 to 4, 4 to 8, or 8 to 12 mg of Compound (I) per day.

The use further includes the administration of 2 to 4 mg of Compound (I), especially when administered daily.

More specifically, the use comprises administering 4 to 8 mg of Compound (I), especially when administered daily.

The use further includes the administration of 8 to 12 mg of Compound (I), especially when administered daily.

It is preferred that the use comprises the administration of 2 mg of Compound (I), especially when administered daily.

It is preferred that the use comprises the administration of 4 mg of Compound (I), especially when administered daily.

It is preferred that the use comprises the administration of 8 mg of Compound (I), especially when administered daily.

It is understood that the insulin sensitizer, for example Compound (I), the insulin secretion promoter and the α-glucosidase inhibitory antihyperglycaemic agent are each administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates of the relevant pharmaceutical active ingredients. . In some instances, the name of the relevant insulin secretion promoter and an aglucosidase inhibitory antihyperglycaemic agent that may be associated with the appropriate pharmaceutical form of the active agent is used herein; It is to be understood that all pharmaceutically acceptable forms of said active ingredients as such are included within the scope of this invention.

Suitable, pharmaceutically acceptable salt forms of the insulin sensitizer, for example Compound (I), include those described in the above patents and patent applications, such as EP 0 306 228 and WO9405 659 for Compound (I). A preferred pharmaceutically acceptable salt is maleate.

Suitable, pharmaceutically acceptable solvated forms of the insulin sensitizer, for example compound (I), include the solvate forms described in the aforementioned patents and patent applications, such as EP 0 306 228 and WO94 / 05 659 for compound (I), in particular hydrates.

Suitable, pharmaceutically acceptable forms of the insulin secretion promoter and α-glucosidase inhibitor antihyperglycaemic agent depend on the promoter used, including all known, pharmaceutically acceptable forms of selected forms of the individual insulin secretion promoters. These derivatives, or references thereto, can be found in basic reference guides such as British and American Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), The Extra Pharmacopoeia (London, The.

(E.g., 31st edition, page 341 and pages cited therein).

Insulin sensitizers, such as compound (I), and / or pharmaceutically acceptable forms thereof, can be prepared by known methods, for example, methods disclosed in the aforementioned patents and patent applications, for compound (I), for example in EP 0 306 228 and WO94 / 05 The disclosures of said patents and patent applications, for example EP 0 306 228 and WO94 / 05 659 are incorporated herein by reference.

Compound (I) may exist in one or more tautomeric forms; all such forms are included in the term compound (I) whether they are individual tautomeric forms or mixtures thereof. Compound (I) has a chiral carbon atom and can therefore exist in up to two stereoisomeric forms; the term compound (I) includes all isomeric forms, whether individual isomers or mixtures of isomers, including racemates.

The insulin secretion promoter and the α-glucosidase inhibitory antihyperglycaemic agent are prepared by known methods, for example, by methods which can be found or referenced, in basic reference guides such as British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale. The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, see 31st edition, page 341 and pages cited therein).

The term condition associated with diabetes mellitus includes those associated with a pre-diabetic condition, conditions associated with diabetes mellitus itself, and conditions of complications associated with diabetes mellitus.

The term conditions associated with a pre-diabetic condition include conditions such as insulin resistance, including hereditary insulin resistance, impaired glucose tolerance, and hyperinsulinemia.

The term conditions associated with self diabetes mellitus include hyperglycemia, insulin resistance, including acquired insulin resistance, and obesity. Other conditions associated with self diabetes mellitus include hypertension and cardiovascular disease, in particular atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome, steroid-induced insulin resistance, and pregnancy diabetes.

The term complication associated with diabetes mellitus includes renal diseases, especially renal diseases associated with diabetes II. type, neuropathy and retinopathy.

Kidney diseases associated with II. types of diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, and last degree of kidney disease. Other kidney diseases associated with II. type diabetes include nephrotic syndrome.

To avoid misunderstanding of the expression of scalar quantities, including mg amounts of compound (I) in a pharmaceutically acceptable form, the scalar amount refers to compound (I) per se; for example, 2 mg of Compound (I) as a maleate (addition salt) is an amount of the maleate salt of Compound (I) containing 2 mg of Compound (I).

Diabetes mellitus is preferably II. type diabetes.

The particularly favorable effect in controlling glycemia by the treatment according to the invention, found in comparative trials, appears to be a synergistic effect, the effect being greater than the sum of the effects of the individual active substances.

Glycemic control can be characterized by conventional methods, for example, by determining the glycemic index typically used, for example, dietary plasma sugar or glycosylated hemoglobin (Hb A 1c). These parameters are determined by conventional procedures, for example those described by Tuescher A., Monitoring the Diabetic Patient with Glycosylated Hemoglobin Measurements, Clinical Products 1988.

In a preferred embodiment, the dosage level of each of the active ingredients when used for the treatment of the present invention is lower than would be required for the same control of blood glucose for only the sum of the effects of the individual substances.

Preferably, the insulin sensitizer is used as the first agent to be administered.

It is preferred that the insulin secretion promoter be used as the second agent administered.

It is preferred that the α-glucosidase inhibitor be used as the third agent administered.

Treatment according to the invention has also been shown to improve (compared to the effect of the individual agents) levels of higher serum goat glycosylated end products (AGE), leptin and serum lipids, including total cholesterol, HDL-7cholesterol, LDL-cholesterol, including the proportions of these substances.

In the use according to the invention, the active ingredients are preferably administered in the form of a pharmaceutical composition. It has already been stated that the pharmaceutical compositions may comprise all or any of the drug ingredients.

One embodiment of the invention may accordingly comprise a pharmaceutical composition comprising an insulin sensitizer, such as Compound (I) in an amount of especially 2 to 12 mg, an insulin secretion promoter, an aglucosidase inhibitory antihyperglycaemic agent, and a pharmaceutically acceptable carrier for said active agents.

Said pharmaceutical compositions may be prepared by mixing an insulin sensitizer, such as compound (I), in an amount in particular of 2 to 12 mg, an insulin secretion promoter, an α-glucosidase inhibitory antihyperglycaemic agent and a pharmaceutically acceptable carrier therefor.

The pharmaceutical composition is usually formulated to be suitable for oral administration. However, it may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration.

The pharmaceutical compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitution powders, or in the form of liquid preparations such as oral or sterile parenteral solutions or suspensions.

In order to achieve reliability in drug delivery, it will be appreciated that the pharmaceutical composition of the invention will be in unit dosage form.

Unit dosage forms for oral administration may be tablets or capsules, and the pharmaceutical composition may contain commonly used excipients and additives such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, for example sodium lauryl sulfate.

Said pharmaceutical compositions are preferably in unit dosage form in an amount corresponding to the respective daily dose.

Preferred dosages of insulin sensitizers include those disclosed in the aforementioned patents and patent applications.

Preferred unit doses of compound (I) include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of compound (I).

The compounds of this invention may be administered 1 to 6 times daily, most preferably once or twice daily.

Single doses of compound (I) are 2 mg.day ^-1 , 4 mg.day ^-1 , including 2 mg twice daily, and 8 mg.day ^-1 , including 4 mg twice daily.

Preferred dosages include unit doses of an insulin secretory promoter, for example, a sulfonylurea, or α-glucosidase inhibitor hyperglycemic agent, including known dosages by known unit doses for these compounds as described or referred to in basic manuals such as British and American Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, see 31st edition, page 341 and pages cited therein).

Typical daily dosages of sulfonylureas such as glibenclamide are in the range of 2.5 to 20 mg, such as 10 mg twice daily or 20 mg once daily; a typical daily dose of glipizide is in the range of 2.5 to 40 mg; a typical daily dose of gliclazide is in the range of 40 to 320 mg; a typical daily dose of tolazamide is in the range of 100 to 1000 mg per day; a typical daily dose of tolbutamide is in the range of 1000 to 3000 mg; a typical daily dose of chlorpropamide is. in the range

Even from 100 to 500 mg and a typical daily dose of glicvidone is in the range of 15 to 180 mg.

Repaglinide can usually be taken in amounts of from 0.5 mg to 4 mg and usually with food, up to typically a maximum daily dose of 16 mg per day.

For the dosage of α-glucosidase inhibitory antihyperglycaemic agents, a typical daily dose of acarbose will be in the range of 50 to 600 mg, for example 100 mg or 200 mg per day.

Solid oral pharmaceutical compositions may be prepared by conventional methods of mixing, filling or tabletting. When a large proportion of fillers is used, the mixing operation can be repeated to mix the active ingredient in the pharmaceutical composition. Such operations are well known in the art. The tablets may be coated according to methods well known in the pharmaceutical art, particularly coatings that dissolve in the intestinal tract.

Oral liquid pharmaceutical preparations may take the form of, for example, emulsions, syrups or elixirs, or may be in the form of dry preparations for reconstitution (prior to use) in water, or other suitable carrier. These liquid preparations may contain conventional additives such as dispersants, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifiers such as lecithin, sorbitan monooleate, or acacia; non-aqueous carriers (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as glycerol esters, propylene glycol, or ethanol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; if desired, they may contain commonly used flavorings and / or colorants or pigments.

Liquid unit dosage forms for parenteral administration are prepared from said active compounds and a sterile carrier; depending on the concentration chosen, the active compounds may be dissolved or suspended in a carrier. To prepare solutions, the active compound is dissolved in water for injection, before being filled into a suitable vial or vial, and sterilized by filtration prior to sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and buffers may be dissolved in the carrier. To enhance stability, the pharmaceutical compositions may be freeze-dried after filling and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, but compound (I) is suspended in the carrier instead of being dissolved and sterilization cannot be accomplished by filtration. The compound may be sterilized by exposure to ethylene oxide prior to dispersion in a sterile carrier. Preferably, a surfactant is included in the carrier to facilitate uniform distribution of the compound in the suspension.

The pharmaceutical compositions may contain from 0.01% to 99% by weight, preferably from 10 to 60% by weight of the active ingredient, depending on the mode of administration.

If desired, the pharmaceutical compositions may also be packaged with attached written or printed instructions for use.

Pharmaceutical compositions are formulated in accordance with general principles, such as those disclosed in standard reference texts such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example see the 31 ^st Edition, 341 and pages therein) or in Cosmeticology (Harry, Leonard Hill Books).

In another embodiment, the invention also includes a pharmaceutical composition comprising an insulin sensitizer, such as compound (I), in particular 2 to 12 mg thereof, an insulin secretion promoter, an α-glucosidase inhibitory antihyperglycaemic agent, and a pharmaceutically acceptable carrier thereof. therapeutic preparation.

In another embodiment, the invention includes the use of an insulin sensitizer such as Compound (I), in particular 2 to 12 mg thereof, an insulin secretion promoter, an α-glucosidase inhibitory antihyperglycaemic agent, and a pharmaceutically acceptable carrier thereof. conditions associated with diabetes mellitus.

The invention in a further embodiment, a pharmaceutical composition comprising an insulin sensitiser such as Compound (I) especially 2 to 12 mg thereof, an insulin secretagogue, α-glucosidase inhibitor antihyperglycaemic agent t 'and a pharmaceutically acceptable carrier therefor ¹ compounds for use in the treating diabetes mellitus and conditions associated with diabetes mellitus.

The range of 2 to 4 mg includes the range of 2.1 to 4.2.2 to 4.2.3 to 4.2.4 to 4, 2.5 to 4, 2.6 to 4, 2.7 to 4.2 , 8 to 4, 2.9 to 4, or 3 to 4 mg.

The range 4-8 mg includes the range 4.1-8, 4.2-8, 4.3-8, 4.4-8, 4.5-8, 4.6-8, 4.7-8.4. , 8 to 8, 4.9 to 8, 5 to 8, 6 to 8, or 7 to 8 mg.

-11 The range of 8 to 12 mg includes the range of 8.1 to 12, 8.2 to 12, 8.3 to 12, 8.4 to 12,

8.5 to 12, 8.6 to 12, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12, 10 to 12, or 11 to 12 mg.

No adverse toxicological effects are expected within the dosage ranges of the pharmaceutical compositions of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Pharmaceutical composition of compound (I)

Concentrate Preparation: A tableted concentrate was prepared from the following materials.

Pharmaceutical composition component Quantity (%) Grind compound (I) as a maleic acid salt 13.25 (pure maleate) Sodium starch glycolate 5.00 Hydroxypropyl methylcellulose 2910 5.00 Microcrystalline cellulose (Avicel PH 102) 20.0 Lactose monohydrate, normal grade to 100 Purified water *

* water escapes during processing

Then the concentrate was formulated into tablets using:

tablet strength (pharmacologically) 1.0 mg 2.0 mg 4.0 mg 8.0 mg active ingredient: compound (I), maleate granulate concentrate amount (mg per tablet) 10.00 20.00 40.00 80.00 other ingredients: sodium starch glycolate 6.96 6.46 5.46 10.92 microcrystalline cellulose (Avicel PH 102) 27.85 25.85 21.85 43.70 lactose monohydrate (Pharmatose DCL15) 104.44 96.94 81.94 163.88 magnesium stearate 0.75 0.75 0.75 1.50 weight of the tablet core together 150.0 150.0 150.0 300.0 aqueous coating material 4.5 4.5 4.5 9.0 total weight of coated tablet 154.5 154.5 154.5 309.0

Pharmaceutical formulations of other active ingredients have been prepared as described in the publications mentioned above.

Claims (22)

Use of an insulin sensitizer, an insulin secretion promoter and an α-glucosidase inhibitory antihyperglycaemic agent for the manufacture of a medicament for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in mammals. The use of claim 1, wherein the insulin secretion promoter is glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, glicvidone, glisentide, glizolamide, glizoxepid, glycopyridide, glycopyridide, glycopyridide, glycopyridide. The use of claim 1, wherein the α-glucosidase inhibitor antihyperglycemic agent is acarbose, emiglitate and miglitol. Use according to any one of claims 1 to 3, wherein the insulin sensitizer is a 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione compound (I). Use according to any one of claims 1 to 4, which comprises administering 2 to 12 mg of compound (I). The use of any one of claims 1 to 5, which comprises administering 2 to 4.4 to 8, or 8 to 12 mg of Compound (I). • I The use according to any one of claims 1 to 6, which comprises administering 2 to 4 mg of Compound (I). Use according to any one of claims 1 to 6, which comprises administering 4 to 8 mg of compound (I). Use according to any one of claims 1 to 6, which comprises administering 8 to 12 mg of compound (I). Use according to any one of claims 1 to 6, which comprises administering 2 mg of compound (I). The use of any one of claims 1 to 6, which comprises administering 4 mg of Compound (I). The use of any one of claims 1 to 6, which comprises administering 8 mg of Compound (I). The use of claim 1, wherein the insulin sensitizer is selected from the group consisting of: (+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2 , 4-thiazolidinedione - troglitazone, 5- [4 - [(1-methylcyclohexyl) methoxy] benzyl] thiazolidin-2,4-dione-ciglitazone, 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidin-2, 4-dione - pioglitazone, or 5 - [(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl] thiazolidin-2,4-dione -englitazone, or a pharmaceutically acceptable form thereof. 14. A pharmaceutical composition comprising an insulin sensitizer, an insulin secretion promoter, an α-glucosidase inhibitory antihyperglycaemic agent, and a pharmaceutically acceptable carrier therefor. 15. A pharmaceutical composition according to claim 14, wherein the insulin secretion promoter is a sulfonylurea. A pharmaceutical composition according to claim 14 or 15, wherein the insulin secretion promoter is glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, glicvidone, glisentide, glizolamide, glizolamide, glizolamide. , glycylamide or repaglinide. 17. The pharmaceutical composition of claim 14 wherein the biguanide is metformin, buformin or phenformin. A pharmaceutical composition according to any one of claims 14 to 17, wherein the insulin sensitizer is Compound (I). Pharmaceutical composition according to any one of claims 14 to 17, characterized in that it contains 2 to 12 mg of compound (I). A pharmaceutical composition comprising an insulin sensitizer, an insulin secretion promoter, an α-glucosidase inhibitory antihyperglycaemic agent, and a pharmaceutically acceptable carrier for said active agents for use as an active therapeutic agent. A pharmaceutical composition comprising an insulin sensitizer, an insulin secretion promoter, an α-glucosidase inhibitory antihyperglycaemic agent, and a pharmaceutically acceptable carrier for said active agents for use in the treatment of diabetes mellitus and conditions associated with diabetes mellitus. A pharmaceutical composition according to any one of claims 14, 20 or 21, wherein the insulin sensitizer is selected from: